The enzyme dipeptidyl peptidase IV, herein abbreviated DPP-IV (and elsewhere as DP-IV, DP-4 or DAP-IV) and also known by the classification EC. 3. 4. 14. 5, is a serine protease (Barrett A. J. et al., Arch. Biochem. Biophys., 1995, 247-250), which cleaves the N-terminal dipeptide from peptides that begin with the sequence H-Xaa-Pro-Y or H-Xaa-Ala-Y wherein Xaa represents any lipophilic amino acid, Pro represents proline, and Ala represents alanine (Heins J., et al., Biochim. et Biophys. Acta 1988, 161). DPP-IV is widely distributed and found in a variety of mammalian tissues such as kidney, liver and small intestine (Hegen M. et al., J. Immunol., 1990, 2908-2914). DPP-IV was first identified as a membrane-bound protein. More recently a soluble form has been identified (Duke-Cohan J. S. et al., J. Biol. Chem., 1995, 14107-14114). According to the recently published study and report, it was revealed that such a soluble form of DPP-IV has the same structure and function as a membrane-bound form of the enzyme and is found without a certain membrane-bound domain in blood (Christine D. et. al, Eur. J. Biochem., 2000, 5608-5613).
Initial interest in DPP-IV has focused on its role in the activation of T lymphocytes. DPP-IV responsible for the activation of T lymphocytes was specifically designated CD26. With the report showing that CD26 binds to or interacts with human immunodeficiency virus (HIV) (Guteil W. G. et al., Proc. Natl. Acad. Sci., 1994, 6594-6598), it was proposed that DPP-IV inhibitors could be useful in the treatment of AIDS (Doreen M. A. et al., Bioorg. Med. Chem. Lett., 1996, 2745-2748).
In addition to a critical role participating in the immune system, the main function of DPP-IV stems from its peptidolytic activity as described above. Attention was particularly given to the role of DPP-IV as it is found that DPP-IV is a key enzyme implicated in the degradation of glucagon-like protein-1 (hereinafter, referred to as “GLP-1”) in the small intestine (Mentlein R. et al., Eur. J. Biochem., 1993, 829-835). GLP-1 is the 30 amino-acid peptide hormone which is secreted by intestinal L cells as a response to food intake of the small intestine (Goke R. et. al, J. Biol. Chem., 1993, 19650-19655). Since GLP-1 is known to have potentiating effects on the action of insulin in the control of postprandial blood glucose levels (Hoist J. J. et al., Diabetes Care, 1996, 580-586), it was postulated that DPP-IV inhibitors might also be usefully employed in the treatment of type 2 diabetes. Based on this assumption, an early form of the DPP-IV inhibitor was developed with some reports demonstrating the therapeutic effectiveness of a medicine in animal experiments (Pauly R. P. et al., Metabolism, 1999, 385-389). Further, DPP-IV-deficient mice or rats maintained GLP-1 activity and high insulin levels, resulting in decreased blood glucose levels and such a genetic disruption or mutation of the DPP-IV gene exhibited no significant effect on the survival of individual animals (Marguet D. et al., Proc. Natl. Acad. Sci., 2000, 6874-6879). As a consequence, it was proposed that DPP-IV is feasible as a potent therapeutic agent for the treatment of type 2 diabetes, which resulted in accelerated research and development of the DPP-IV inhibitor.
Binding of GLP-1 with a receptor in a variety of tissues results in satiety (feelings of fullness), delayed gastric emptying, and facilitated growth of pancreatic beta-cells. Therefore, clinical trials for the treatment of type 2 diabetes are gradually increasing through intravenous administration of GLP-1 per se (Verdich C. et al., J. Clin. Endocrinol. Metab., 2001, 4382-4389). An in vivo half-life of GLP-1 is merely 2 min (Kieffer T. J., et al., Endocrinology, 1995, 3585-3596), so such a short half-life is a major obstacle to direct use of GLP-1 as a therapeutic agent. Since then, numerous research groups and institutions have made many attempts toward derivatization of GLP-1, resulting in development and commercialization of a peptide which is capable of protracting the short in vivo half-life (Deacon C. F., Diabetes, 2004, 2181-2189). However, such a GLP-1 derivative still suffers from a fundamental limitation in that it is an injectable formulation. Further, a great deal of interest has been increasingly focused on development of an efficient DPP-IV inhibitor, due to the fact that active GLP-1 (7-36) is degraded by DPP-IV and then converted into inactive GLP-1(9-36) only within a short period of time, e.g. 2 min.
The beginning in the development of DPP-IV inhibitors was similar to the development trend of other inhibitors. That is, most of the research results were for substrate analogues. A representative one of these substrate analogues is a dipeptide derivative which was obtained as the product of the early research which was performed on a parent nucleus having a structure similar to that of Proline (Pro), based on the fact that DPP-IV exhibits pronounced affinity for a peptide containing a certain amino acid Proline (Chinnaswamy T. et al., J. Biol. Chem., 1990, 1476-1483). Typical examples of Proline-like structures include pyrrolidide and thiazolidide, and derivatives containing these parent nucleus compounds exhibit reversible and competitive inhibitory activity for the DPP-IV enzyme (Augustyns K J L., et al., Eur. J. Med. Chem., 1997, 301-309).
Among products of such extensive research and development, there are continuing experiments on the action mechanism and efficacy of certain compounds, specifically Val-Pyr (Valine-Pyrrolidide), Ile-Thia (Isoleucine-Thiazolidide), and the like. Particularly, a great deal of attention has been focused on Ile-Thia, because the Val-Pyr structure exhibited relatively poor inhibitory activity on DPP-IV (Hanne B. R., et al., Nat. Struct. Biol., 2003, 19-25), which as such prompted intensive research and study on derivatives of the Ile-Thia compound.
Out of the Ile-Thia derivative compounds focused and obtained by the above-mentioned research and study, a compound having the most prominent activity was beta-amino acid thiazolidide series which was attempted to be developed by Merck & Co., Inc. However, according to the results of pharmacodynamic and pharmacokinetic experiments performed in rats, the obtained compound exhibited significantly low bioavailability in conjunction with an apparent limitation in the inhibition of enzymatic activity (Jinyou Xu, et al., Bioorg. Med. Chem. Lett., 2004, 4759-4762). As a consequence, further development on compounds of this class was discontinued due to profound disadvantages.
During the above-mentioned investigation, Merck noticed that a beta-amino acid, in addition to a thiazolidide parent nucleus, is also a key factor having significant effects on the DPP-IV inhibitory activity. This finding was applied to the approach for substitution of the thiazolidide parent nucleus with a different parent nucleus compound (Linda L. B., et al., Bioorg. Med. Chem. Lett., 2004, 4763-4766). With such a subsequent research, a variety of derivatives having substitution of the thiazolidide parent nucleus with a piperazine parent nucleus were synthesized with drug efficacy testing and pharmacodynamic studies. Unfortunately, the piperazine derivatives of Merck still suffered from significantly poor bioavailability. According to the compound optimization to cope with such a disadvantage, the product MK-0431 (trade name: JANUVIA) was developed with modification of a piperazine moiety to a triazolopiperazine moiety. This product is now commercially available under new drug approval by US FDA in 2006. Further, subsequent to MK-0431, a compound with incorporation of a diazepanone moiety (seven-membered ring) is currently under development (WO 2004037169; WO2005011581; WO2006104997; and Bioorg. Med. Chem. Lett., 2007, 49-52). Particularly according to the article published in the journal (Bioorg. Med. Chem. Lett., 2007, 49-52), it was demonstrated that imidazolone (five-membered ring) and piperazinone (six-membered ring) exhibit remarkably lower in vitro activity, as compared to diazepanone, thus resulting in an intensive focus on the optimization of diazepanone.

As a result of a variety of extensive and intensive studies and experiments to solve the problems as described above and to achieve the optimization of a compound of interest, the inventors of the present invention discovered that when a substitution including a hetero atom is made on a piperazinone moiety, the thus-modified compound not only has excellent DPP-IV inhibitory activity, but also is capable of achieving significantly improved bioavailability as compared to a conventional DPP-IV inhibitor, and then succeeded in synthesis of a novel heterocyclic compound containing a beta-amino group. The present invention has been completed based on these findings.